PROJECT SUMMARY Deficits in dopamine signaling are a common feature of various prevalent neuropsychiatric disorders, including substance use disorders, which have been linked to reduced dopamine D2-type receptor (DRD2/3) availability (binding potential: BPND) in the striatum. In contrast, higher BPND has been linked to resilience to addiction in humans and to greater success of behavioral treatments for stimulant dependence. Thus, enhancing striatal dopaminergic DRD2/3 signaling may be a useful therapeutic approach for addictive disorders, but D2 receptor agonists have failed as therapies for addictions, possibly due to chronic DRD2/3 downregulation. Because of the potential therapeutic value of DRD2/3 upregulation, the goal of this project is to test the ability of a medication, varenicline, to produce striatal DRD2/3 upregulation. Subchronic varenicline administration produces striatal DRD2/3 upregulation in drug-nave rats, but whether varenicline has the same effect in humans is not known. Varenicline also improves cognitive performance in human subjects, and because cognitive deficits can undermine behavioral treatments, improvement with varenicline, either through DRD2/3 upregulation or another mechanism, may provide a useful adjunct to behavioral treatments for addictions as well as other disorders which feature deficits in DRD2/3. We will assess the effects of subchronic varenicline treatment in healthy human subjects with methamphetamine-use disorder, using a placebo-controlled double-blind design. The dependent variables will be DRD2/3 BPND in striatum, measured using positron emission tomography, and cognitive performance in tests of attention, memory, inhibitory control, and impulsive choice. Positive findings in this pilot/feasibility study would identify varenicline as the first medication to produce striatal DRD2/3 upregulation in humans, specifically in stimulant users. Especially if accompanied by improvement in cognition, the project would justify targeted studies of varenicline effects on DRD2/3 availability in clinical groups, particularly those with addictions.